Telomeres consist of long TTAGGG nucleotide repeats and associated proteins at the ends of chromosomes that are essential for the maintenance of chromosomal integrity. In order to preserve the chromosome end, the telomerase reverse transcriptase (TERT), its RNA component (TERC) and an ordered protein complex, termed shelterin, consisting of six proteins (gene names: TERF1, TERF2, TINF2, TERF2IP, ACD and POT1) protect the telomere from end-to-end fusion. Telomeric repeats are lost with each cell division, in part due to incomplete replication of the 3" end of the chromosome. Telomeric attrition eventually results in critically short telomeres prompting cellular senescence or cellular crisis, including apoptosis, genomic instability or a reduction in cellular lifespan. 1) Dyskeratosis congenita (DC) study: DC is an inherited bone marrow failure syndrome (IBMFS) and cancer predisposition disorder characterized by abnormalities in telomere biology and caused by germ-line mutations in one of several genes in the telomere pathways. We recently showed that telomere length, as measured by flow cytometry-FISH was both sensitive and specific for differentiation DC from other IBMFS. Identifying novel genes which might account for the 60% of DC patients who currently do not have detectable mutations in DKC1, TERC or TERT is one of the major goals of this study. Our recently completed a linkage study which has identified TINF2 as mutated in several families with DC. This study also focuses on careful clinical phenotyping. A comprehensive study of dysmorphology in DC is also underway. These studies will provide more specific data on genotype-phenotype interactions and aid in diagnosis of DC. 2) Telomere length in target tissues: These are a set of small, methodological studies that seek to clarify intra-individual variability in telomere length with the ultimate goal being improved understanding of comparability when different cell types and methods of telomere length determination are employed. Epidemiologic studies typically use DNA isolated from either blood or buccal cells, yet direct comparisons of telomere length in blood and buccal cell DNA have not been published. This study will evaluate intra- and inter- individual variation in telomere length in blood, buccal cell and fibroblast DNA in subjects enrolled in the inherited bone marrow failure syndromes study. It will also study the telomere length differences between buccal cell and blood DNA in healthy controls from an ovarian cancer study. 3) Telomere length as a risk factor for prostate cancer: Telomeres, telomere shortening and telomerase activity have emerged as important factors in prostate carcinogenesis. The earliest phase of human prostate carcinogenesis may proceed as a consequence of chromosomal instability mediated by shortened, dysfunctional telomeres. This is part of a case-control study of prostate cancer from the PLCO cohort. Telomere length was determined on 1200 controls and 700 cases of advanced prostate cancer Strong associations between telomere length and prostate cancer risk were not identified. However, longer telomeres were associated with a healthier lifestyle. 4) Novel genetic determinants of telomere length: The same subjects described in 3 were also part of a genome-wide association study (CGEMS, Cancer Genetic Markers of Susceptibility). In collaboration with Drs. Immaculata DeVivo and David Hunter (Harvard School of Public Health), we will add 1200 healthy controls from the Nurse"s Health Study who were part of the CGEMS breast cancer whole-genome scan. We are evaluating the relationship between genetic variants measured on the same platform in the CGEMS GWAS and telomere length (both measured in the same laboratory) among healthy controls: 1200 men and 1200 women. Lastly, interactions between genotypes affecting telomere length will be assessed in the prostate cancer cases and controls. . 5) Population genetics of telomere genes: We have previously shown that nucleotide diversity is low in genes important in telomere biology. This study will follow-up on those finding by evaluating genetic variation in more than 30 telomere biology genes in 1000 individuals from around the world. Insights into population history and identification of SNPs for genotyping in case-control studies will be possible..